Determination of the Optimal Dose of Ephedrine in Intraoperative Arterial Hypotension of Newborns and Infants up to 6 Months of Age. (EPHEDRINE)

Determination of the Optimal Dose of Ephedrine in Intraoperative Arterial Hypotension of Newborns and Infants up to 6 Months of Age. A Randomized, Controlled, Open-label, Dose Escalation Study.

The incidence of arterial hypotension under general anesthesia using sevoflurane is particularly high in newborns and infants up to 6 months of age. A decrease of 20% of the initial mean blood pressure (mBP) is the definition of significant arterial hypotension in adults and children. In adults, intraoperative arterial hypotension is associated with an increase of intraoperative mortality and a certain neurological morbidity. In infants under 6 months of age, neurological disorders have been reported following general anesthesia. Neurotoxicity of hypnotics is often incriminated as should be the episodes of arterial hypotension.

Current management of hypotension uses vascular filling with crystalloids and vasopressive amines in second intention. Dopamine is the most frequently used amine. Ephedrine can also be used. Ephedrine is particularly interesting because of its action on both α and β receptors and its mode of administration: one dose and peripheral access.

Only one study is available in children from birth to adulthood; it demonstrates a lower hemodynamic response in infants than in adults, when administered a low dose of Ephedrine (0.1 to 0.2 mg/kg). A recent retrospective cohort suggests an under efficacy of low doses and the use of higher doses than those recommended.

The primary objective is to determine the optimal dose of ephedrine (dose of ephedrine associated with a difference of proportion of newborns/infants in therapeutic success of 55%) compare to the reference dose of 0.1mg/kg as a first line treatment of intraoperative arterial hypotension.

Secondary objectives:

• Return to a mBP superior to 38mmHg post Ephedrine administration.
• To assess occurrence of hypoxemic events during anesthesia.
• To assess tolerance of ephedrine. One hundred and twenty newborn and infants up to 6 months of age will be recruited in 3 sites of the Rhone Alpes Auvergne area over 24 months.

Study Overview

• Status: Completed
• Conditions: Infant, Newborn; Intraoperative Arterial Hypotension
• Intervention / Treatment: Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG; Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.1 mg/kG.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • Hôpital d'Estaing
  • Lyon, France
    • Hospices Civils de Lyon
  • Saint Etienne, France, 42055
    • Hopital Nord

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 10 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newborns or infants < 6 months of age,
• boys and girls,
• premature or not,
• requiring general anesthesia induced by sevoflurane
• who presents during anesthesia a decrease of blood pressure superior to 20% of the basal mBP (measured prior to surgery) despite of vascular filling with sodium chloride 0.9% (10mL/kg during 10 min).
• Written, informed consent obtained from the 2 parents

Exclusion Criteria:

• Allergy to Ephedrine.
• Emergency surgery.
• Patient having previously received other vasopressive amines.
• Use of other indirect sympathomimetic drug such as phenylpropanolamine, phenylephrine, pseudoephedrine and methylphenidate.
• Premedication with clonidine
• Congenital heart disease
• IV-induced anesthesia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ephedrine, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG; Dose escalation: 6 successive cohorts with a maximal increasing dose	Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG
Active Comparator: Ephedrine, dose : 0.1 mg/kG, reference dose; Reference dose	Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.1 mg/kG.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Therapeutic success is defined as a mBP superior to 55% of the basal mBP (prior to anesthesia) within 10 minutes post Ephedrine administration	Continuous monitoring within 10 minutes post-administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Return to a mBP superior to 38mmHg within 10 minutes post Ephedrine administration		Continuous monitoring within 10 minutes post-administration
Variations of O2 saturation in cerebral tissue (number of desaturations, evolution under treatment) using a Near Infrared Spectroscopy (NIRS) technology		Continuous monitoring within 10 minutes post-administration
Tolerance of Ephedrine: occurrence of serious adverse events	Clinical examination focusing specifically on heart rate and hypertension	During 3 days post-administration

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Mathilde de Queiroz Siqueira, MD, Service d'anesthésie pédiatrique et obstétricale, Hôpital Femme Mère Enfant, 59 boulevard Pinel - 69 677 BRON Cedex

Publications and helpful links

General Publications

• Szostek AS, Boucher P, Subtil F, Zerzaihi O, Saunier C, de Queiroz Siqueira M, Merquiol F, Martin P, Granier M, Gerst A, Lambert A, Storme T, Chassard D, Nony P, Kassai B, Gaillard S. Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial. Trials. 2021 Mar 12;22(1):208. doi: 10.1186/s13063-021-05155-2.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): September 5, 2020
• Study Completion (Actual): September 5, 2020

Study Registration Dates

• First Submitted: February 27, 2015
• First Submitted That Met QC Criteria: March 4, 2015
• First Posted (Estimate): March 10, 2015

Study Record Updates

• Last Update Posted (Actual): July 27, 2021
• Last Update Submitted That Met QC Criteria: July 26, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: pediatric; general anesthesia; ephedrine; intraoperative arterial hypotension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypotension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Central Nervous System Stimulants; Sympathomimetics; Vasoconstrictor Agents; Nasal Decongestants; Pharmaceutical Solutions; Ephedrine; Pseudoephedrine
• Other Study ID Numbers: 69HCL14_0248; 2014-004190-16 (EudraCT Number)